This phase II trial studies how well ofatumumab in combination with cyclophosphamide, doxorubicin hydrochloride, vincristine sulfate, and dexamethasone alternating with ofatumumab in combination with cytarabine and methotrexate works in treating patients with newly diagnosed mantle cell lymphoma (MCL). Monoclonal antibodies, such as ofatumumab, may interfere with the ability of cancer cells to grow and spread. Drugs used in chemotherapy, such as cyclophosphamide, doxorubicin hydrochloride, vincristine sulfate, dexamethasone, cytarabine, and methotrexate, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving ofatumumab together with alternating regimens of combination chemotherapy may kill more cancer cells.

Evaluated according to the International Working Group Response criteria as reported by Cheson et al. and the revised Cheson criteria.

Secondary Outcome Measures:

Ability of the induction and consolidation therapy to get 70% of patients to autologous stem cell transplantation [ Time Frame: Up to 6 weeks after the last dose of ofatumumab-chemotherapy ] [ Designated as safety issue: No ]

Estimated using simple relative frequencies. The corresponding 95% confidence intervals will be computed using the method proposed in Clopper and Pearson.

Change in surface CD20 levels, Ki67, and additional cytogenetic abnormalities [ Time Frame: Baseline to up to 3 years ] [ Designated as safety issue: No ]

Association between change in CD20 levels, Ki67, and cytogenetic abnormalities and ORR, CRR, TTP, PFS, and OS will be statistically assessed using logistic regression. Wald tests of the model effects will be performed to assess statistical significance.

Change of serum complement component (C)3, C4, and complement CH50 (CH50) levels [ Time Frame: Baseline to up to 3 years ] [ Designated as safety issue: No ]

Association between change in serum C3, C4, and CH50 levels and ORR, CRR, TTP, PFS, and OS will be statistically assessed using logistic regression. Wald tests of the model effects will be performed to assess statistical significance.

Frequency of adverse events [ Time Frame: Up to 3 years ] [ Designated as safety issue: Yes ]

Evaluated using National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. Toxicity rates will be estimated using simple relative frequencies. The corresponding 95% confidence intervals for the estimated probabilities will be computed using the method proposed in Clopper and Pearson.

Association between MRD and TTP, PFS, and OS will be statistically assessed using logistic regression. Wald tests of the model effects will be performed to assess statistical significance.

Overall survival (OS) [ Time Frame: From baseline until death from any cause, assessed up to 3 years ] [ Designated as safety issue: No ]

Estimated distributions obtained using the Kaplan-Meier method. Estimates of quantities such as median survival will be obtained. Corresponding confidence intervals using the methodology of Brookmeyer and Crowley will be computed.

Estimated distributions obtained using the Kaplan-Meier method. Estimates of quantities such as median survival will be obtained. Corresponding confidence intervals using the methodology of Brookmeyer and Crowley will be computed.

Relationship between proliferation signature and clinical outcome will be compared using the log-rank test. Cox proportional hazards model regression will be utilized for multivariate analyses.

Proportion of patients who experience complete remission as assessed by HSFCM [ Time Frame: Up to 3 years ] [ Designated as safety issue: No ]

Established when all CR criteria are met and negative flow cytometry examination of peripheral blood and bone marrow biopsy/aspiration collected at baseline, before courses 3 and 5, within 3 weeks after course 6, on day 100 (if HDC-ASCT eligible), and then every 6 months for 3 years.

Time-to-tumor progression (TTP) [ Time Frame: From baseline until objective tumor progression, as assessed up to 3 years ] [ Designated as safety issue: No ]

Estimated distributions obtained using the Kaplan-Meier method. Corresponding confidence intervals using the methodology of Brookmeyer and Crowley will be computed.

COURSES 1, 3, and 5 (O-HyperCVAD): Patients receive ofatumumab IV on day 1, cyclophosphamide IV over 2 hours every 12 hours for 6 doses on days 3-5, doxorubicin hydrochloride IV continuously over 72 hours on days 6-8, vincristine sulfate IV on days 6 and 13, and dexamethasone IV or PO on days 3-6 and 13-16.

COURSES 2, 4, and 6 (O-HD-MA): Patients receive ofatumumab IV on day 1, methotrexate IV continuously over 24 hours on day 3, and cytarabine IV over 2 hours every 12 hours on days 4-5.

All courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.

Histologically documented mantle cell lymphoma with co-expression of CD20 and CD5 and lack of CD23 expression by immunophenotyping and at least one of the following confirmatory tests: 1) positive immunostaining for cyclin D1; 2) the presence of t(11;14) on cytogenetic analysis; OR 3) molecular evidence of B-cell leukemia/lymphoma 1 (bcl-1)/immunoglobulin heavy locus (IgH) rearrangement

Cases that are CD5-negative and/or CD23-positive will be eligible provided that the histopathology is consistent with mantle cell lymphoma AND positive for cyclin D1, t(11;14), or bcl-1/IgH rearrangement

A diagnosis based on peripheral blood or bone marrow aspirate is allowed; if the diagnosis is based only on blood, in addition to the immunophenotype and molecular confirmation above, a peripheral blood smear must be available for central pathology review; if the diagnosis is based on a bone marrow, the bone marrow core biopsy or aspirate clot tissue block will be submitted to the RPCI Pathology Department: if the tissue block is not available please submit the diagnostic smears for review

Extent of disease: stage I - IV; patients with nodular histology mantle cell lymphoma must have Ann Arbor stage III or IV disease to be eligible

Patients with mantle zone type histology will not be eligible

Patients with other mantle cell histologies are eligible regardless of stage

No active central nervous system (CNS) disease defined as symptomatic meningeal lymphoma or known CNS parenchymal lymphoma; a lumbar puncture demonstrating mantle cell lymphoma at the time of registration to this study is not an exclusion for study enrollment

Patients must be previously untreated

No prior radiation therapy for mantle cell lymphoma

>= 2 weeks since major surgery

No known hypersensitivity to murine products

No medical condition requiring chronic use of high dose systemic corticosteroids (i.e., doses of prednisone higher than 10 mg/day or equivalent)

No human immunodeficiency virus (HIV) infection; patients with a history of intravenous drug abuse or any behavior associated with an increased risk of HIV infection should be tested for exposure to the HIV virus; patients who test positive or who are known to be infected are not eligible; an HIV test is not required for entry on this protocol, but is required if the patient is perceived to be at risk

Non-pregnant and non-nursing; women and men of reproductive potential should agree to use an effective means of birth control

If HBV DNA is negative, patient may be included but must undergo at least every 2 months HBV DNA polymerase chain reaction (PCR) testing from the start of treatment throughout the duration the study

Monitoring during the study is required at least every 2 months and during follow-up at a minimum of every 2-3 months up to 6 months after the last dose

Prophylactic antiviral therapy with lamivudine (3TC) or investigator's preferred antiviral regimen throughout protocol therapy and for 6-12 months thereafter may be initiated at the discretion of the investigator

If the patients' HBV DNA becomes positive during the study, the investigator should manage the clinical situation as per the standard of care of participating institution; the investigator should weigh the risks and benefits of continuing ofatumumab or discontinuing ofatumumab before appropriate treatment decisions are made for that individual patient

Patients must not have a history of cardiac disease, defined as New York Heart Association class II or greater or clinical evidence of congestive heart failure (CHF)

No known hypersensitivity to ofatumumab, humanized antibodies or chemotherapy agents throughout the protocol

Patient or legal representative must understand the investigational nature of this study and sign an Independent Ethics Committee/Institutional Review Board approved written informed consent form prior to receiving any study related procedure

Consult with a physician experience in care and management of subjects with hepatitis B to manage/treat subjects who are anti-hepatitis B core antibody (HBc) positive

Exclusion Criteria:

Prior history of HIV-positivity (routine HIV testing is not required pre-treatment)

Positive serology for hepatitis B (HB) defined as a positive test for HBsAg; in addition, if negative for HBsAg but HBcAb positive (regardless of HBsAb status), a hepatitis B DNA test will be performed and if positive the patient will be excluded

History of allergic reactions attributed to compounds of similar chemical or biologic composition to ofatumumab or other agents used in study

Patients with a "currently active" second malignancy, other than non-melanoma skin cancer or in situ carcinoma of the cervix or breast; patients are not considered to have a "currently active" malignancy if they have completed anti-cancer therapy, are considered by their physician to be at less than 30% risk of relapse and at least 2-5 years have lapsed

Major surgery, other than diagnostic surgery, within 2 weeks

Patients with non-Hodgkin lymphoma (NHL) other than MCL

Patients must not have a history of cardiac disease, defined as New York Heart Association class II or greater or clinical evidence of congestive heart failure; all patients must have a MUGA scan or 2-dimensional (D) echocardiogram indicating an ejection fraction of >= 45% within 42 days prior to registration; the method used at baseline must be used for later monitoring

Unwilling or unable to follow protocol requirements

Any condition which in the Investigator's opinion deems the patient an unsuitable candidate to receive study drug

Received an investigational agent within 30 days prior to enrollment

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Please refer to this study by its ClinicalTrials.gov identifier: NCT01527149